The biomarker core will provide a centralized resource for the rapid, high throughput quantification of transcripts and proteins. Transcripts will be quantified using quantitative PCR (Q-PCR). In addition the Biomarker Core will provide for genome-wide microarray analysis using an lllumina Beadstation. Quantification of protein levels in blood or tissue lysates will be done using a MesoScale Sector Imager or by reverse-phase protein array (RPPA) The biomarker core will serve to provide: 1) quantitative mRNA levels for known genes that are Involved In proliferation and implicated in cancer progression; 2) identification of unique proteins, genes and expression profiles in cells or tissues after a molecular or pharmacologic manipulation; 3) validation of the expression of genes that are initially identified in screening by microan-ays, 4) quantification of protein levels both as an independent validation technique and to determine the relationship between transcript levels and protein levels. Specific Aims 1-4 represent interactions between projects in the SPORE and the Biomarker Core. Specific Aim 1 Metformin for the chemoprevention of endometrial cancer in obese, insulin resistant women. These studies will use both animal models of obesity and conduct a clinical trial using metformin and examine the impact on endometrial cancer. Biomarkers that will be measured include Ki-67, Cyclin A, sFRPI, sFRP4, survivin, EIG121, RALDH2, PR, ER, IGF-1 IGF-1 R. RPPA and microarrays will also be used in these studies. Specific Aim 2. Sfrafegy for the Incorporation of Tissue S/omarkers in the Clinicai Management of Endometrial Cancer Patients. This project will assess the utility of a panel of 7 previously identified biomarkers in a large number of FFPE endometrial samples. This project will also use RPPA to help discover new biomarkers to augment the current biomarker panel. Specific Aim 3 EphA2 Targeting in Uterine Carcinoma. These studies will evaluate the function of EphA2 in cancer and conduct a clinical trial of a novel immuno-conjugate that targets the EphA2 receptor. Q-PCR will assess the biomarkers listed above, markers of angiogenesis, and cell free nucleic acids. Pre-and post- biopsy endometrial will be assayed for the core biomarkers, markers of angiogenesis and EphA2 transcripts. Microarray studies will be conducted to identify both pathways and novel genes regulated by EphA2. Specific Aim 4 Targeting the Pi3K Signaling Pathway in Endometrial Carcinoma. In these studies the Core will examine by RPPA approximately 550 tissue specimens for alteration in the expression and phosphorylation of members of the PISK signaling pathway. Specific Aim 5 is a project within the Biomarker Core that will perform microarray analysis and QPCR validation on approximately 90 samples from patients with HNPCC at baseline and following 3 months of chemoprevention therapy with either oral contraceptives or depot medroxyprogesterone.